Rationally designed BCR-ABL kinase inhibitors for improved leukemia treatment via covalent and pro-/dual-drug targeting strategies.

BACKGROUND: Chronic Myeloid Leukemia (CML) is a blood cancer that remains challenging to cure due to drug resistance and side effects from current BCR-ABL inhibitors. There is an urgent need for novel and more effective BCR-ABL targeting inhibitors and therapeutic strategies to combat this deadly disease. METHOD: We disclose an "OH-implant" strategy to improve a noncovalent BCR-ABL inhibitor, PPY-A, by adding a hydroxyl group to its scaffold. By taking advantage of this OH "hot spot", we designed a panel of irreversible covalent kinase inhibitors and hypoxia-responsive pro-/dual-drugs, and their biological activities were studied in vitro, in cellulo and in vivo. RESULT: The resulting compound B1 showed enhanced solubility and biological activity. B4 achieved sustained BCR-ABL inhibition by forming a stable covalent bond with ABL kinase. Hypoxia-responsive prodrug P1 and dual-drugs D1/D2/D3 demonstrated significant anti-tumor effects under hypoxic conditions. The in vivo studies using K562-xenografted mice showed that B1 displayed superior antitumor activity than PPY-A, while P1 and D3 offered better safety profiles alongside significant tumor control. CONCLUSION: We have successfully developed a chemical biology approach to convert a known noncovalent BCR-ABL inhibitor into more potent and safer inhibitors through covalent and pro-/dual-drug targeting strategies. Our "OH-implant" approach and the resulting drug design strategies have general applicability and hold promise for improvement the performance of various other reported drugs/drug candidates, thereby providing advanced medicines for disease treatment.

Introducing Bi2S3 Interlayer to Synergistically Modify Mo Back Contact and Regulate Bulk Defects in Kesterite Solar Cells.

A suitable interlayer between the Mo back electrode and kesterite absorber layer has been proven to have a positive effect on limiting the bulk defects of the absorber by the constitute diffusion. Here, a thin Bi2S3 layer is used as the back-interface intermediate layer for the first time, this innovative approach allows for simultaneous modification of the back contact and reduction of bulk defects, resulting in improving the power conversion efficiency of the kesterite device from 9.66% to 11.8%. The evaporated Bi2O3 thin films turn into the Bi2S3 interlayers after sintering the Cu2ZnSnS4 precursor thin films. The Bi2S3 interlayer can inhibit the decomposition reaction of back contact and suppress the formation of the secondary phases. It can also optimize the Fermi level offset and promote the separation of the photoinduced carriers, resulting from its characteristic of high work function. Besides, a small part of the Bi element can diffuse into Cu2ZnSn(S, Se)4 film and induce the crystal growth and restrain Zn-related defects, which is attributed to forming the low melting-point liquid BiSex phase during the high-temperature selenization process. The conclusions highlight the bifunction of the thin Bi2S3 intermediate layer, which can provide a new approach to improve the photoelectric conversion efficiency of kesterite solar cells.

Crystallinity Control and Strain Release in Wide-Bandgap Perovskite Film via Seed-Induced Growth for Efficient Photovoltaics.

The seed method stands out as a straightforward and efficient approach for fabricating high-performance perovskite solar cells (PSCs). In this study, we propose the utilization of an antisolvent as an additive to induce crystal seeding, thereby facilitating the growth of wide-bandgap perovskite grains. Specifically, we introduce three commonly used antisolvents─ethyl acetate (EA), isopropanol (IPA), and chlorobenzene (CB)─directly into the perovskite precursor solution to generate perovskite seeds, which serve to promote subsequent nucleation. This antisolvent-crystal seeding method (ACSM) results in increased grain sizes, reduced film defects, and overall improved film quality. Consequently, the power conversion efficiencies (PCEs) of 1.647 eV PSCs with EA, IPA, and CB additives are recorded at 19.86%, 20.61%, and 20.45%, respectively, surpassing that of the reference device with a PCE of 18.83%. Furthermore, the stability of the PSCs prepared through ACSM is notably enhanced. Notably, PSCs optimized with IPA retain 75% of the original PCE after being stored in ambient air conditions (25 °C, RH ∼ 15%) for 30 days, better than the CB-added (64%) and the EA-added devices (53%), while the reference devices only retain 31% of the initial PCE. Moreover, even after continuous thermal annealing at 50 °C for 200 h, IPA-assisted devices demonstrate the best stability, followed by those with CB and EA, with the reference exhibiting the poorest stability.

In Situ Vanadium Modification Induced a Back Interfacial Field Passivation Effect toward Efficient Kesterite Solar Cells beyond 11% Efficiency.

Realization of a high-quality back electrode interface (BEI) with suppressed recombination is crucial for Cu2ZnSn(S,Se)4 (CZTSSe) solar cells. To achieve this goal, the construction of a traditional chemical passivation effect has been widely adopted and investigated. However, there is currently a lack of reports concerning the construction of a field passivation effect (FPE) for the BEI. Herein, considering the characteristic of the negligible difference in ionic radius between Mo (0.65 Å) and V (0.64 Å) as well as the presence of one less valence electron compared to Mo, vanadium (V) was employed and in situ incorporated into the MoSe2 interfacial layer during the deposition of the Mo:V electrode and selenization process. This allowed for the establishment of a desirable in situ VI-FPE interface with p-MoSe2:V/p-CZTSSe at the BEI. The p-type characteristic in MoSe2:V is attributed to the presence of the VMo acceptor; notably, the Fermi energy level of MoSe2:V has shifted downward by 0.62 eV compared to MoSe2, thereby facilitating the formation of an optimized band alignment between MoSe2:V and the absorber. Consequently, the photovoltaic parameters of the cell-FPE have experienced a significant increase due to the enhanced carrier transportation efficiency compared to cell-ref, resulting in a remarkable improvement in efficiency from 8.28 to 11.11%.

Observation of Fast Low-Temperature Oxygen Ion Conduction in CeO2/ß"-Al2O3 Heterostructure.

Semiconductor ion fuel cells (SIFCs) have demonstrated impressive ionic conductivity and efficient power generation at temperatures below 600 °C. However, the lack of understanding of the ionic conduction mechanisms associated with composite electrolytes has impeded the advancement of SIFCs toward lower operating temperatures. In this study, a CeO2/ß″-Al2O3 heterostructure electrolyte is introduced, incorporating ß″-Al2O3 and leveraging the local electric field (LEF) as well as the manipulation of the melting point temperature of carbonate/hydroxide (C/H) by Na+ and Mg2+ from ß″-Al2O3. This design successfully maintains swift interfacial conduction of oxygen ions at 350 °C. Consequently, the fuel cell device achieved an exceptional ionic conductivity of 0.019 S/cm and a power output of 85.9 mW/cm2 at 350 °C. The system attained a peak power density of 1 W/cm2 with an ultra-high ionic conductivity of 0.197 S/cm at 550 °C. The results indicate that through engineering the LEF and incorporating the lower melting point C/H, there approach effectively observed oxygen ion transport at low temperatures (350 °C), effectively overcoming the issue of cell failure at temperatures below 419 °C. This study presents a promising methodology for further developing high-performance semiconductor ion fuel cells in the low temperature range of 300-600 °C.

Modulating secondary growth of perovskite grains through residual solvent evaporation.

Over the past decade, perovskite solar cells (PSCs) have attracted enormous attention due to their high performance. One key to fabricating high-quality perovskite films lies in controlling the volatilization rate of residual solvents during the annealing process. This study systematically investigates how different protective substrates affect the volatilization rate of residual solvent in perovskite films. By adjusting the direction and rate of evaporation, the supersaturation time of the solution was precisely controlled, leading to effective recrystallization of the grains. Concurrently, the annealing time was optimized to enhance film quality further. This optimization aimed to increase crystallinity, reduce defects, and thereby minimize non-radiative recombination centers. Implementing these methodologies, particularly the use of filter paper as a protective substrate during a 2-minute annealing process, significantly improved the fill factor (FF) and open-circuit voltage (VOC) of the PSCs. This led to a remarkable 5.26% improvement in power conversion efficiency (PCE) compared to control devices. The strategies employed in this work demonstrate significant potential in improving PSC film quality. This approach not only advances our understanding of film formation dynamics but also provides a practical guideline for future PSC fabrication.

Cross-talk of Three Molecular Subtypes of Telomere Maintenance Defines Clinical Characteristics and Tumor Microenvironment in Gastric Cancer.

Background: Telomere maintenance takes part in the regulation of gastric cancer (GC) pathogenesis and is essential for patients' clinical features. Though the correlation between a single telomere maintenance-related gene and GC has previously been published, comprehensive exploration and systematic analysis remain to be studied. Our study is aimed at determining telomere maintenance-related molecular subtypes and examining their role in GC. Methods: By analyzing the transcriptome data, we identified three telomere maintenance-associated clusters (TMCs) with heterogeneity in clinical features and tumor microenvironment (TME). Then, we screened five prognostic telomere maintenance-related genes and established corresponding TM scores. Additionally, the expression level and biological function of tubulin beta 6 class V (TUBB6) were validated in GC tissues and cells. Results: TMC1 was correlated with EMT and TGF-beta pathway and predicted low tumor mutation burden (TMB) as well as bad prognostic outcomes. TMC3 was associated with cell cycle and DNA repair. In terms of TMB and overall survival, TMC3 exhibited opposite results against TMC1. Significant heterogeneity was observed between TMCs. TUBB6 was upregulated and could promote GC proliferation, migration, and invasion. Conclusion: Altogether, combining bioinformatics and functional experiments, we identified three molecular subtypes based on telomere maintenance-associated genes in GC, which could bring new ideas and novel biomarkers to the clinic.

Tumor-derived extracellular vesicles as a biomarker for breast cancer diagnosis and metastasis monitoring.

It is imperative to explore biomarkers that are both precise and readily accessible in the comprehensive management of breast cancer. A multicenter cohort, including 512 breast cancer patients and 198 nonneoplastic individuals, was recruited to detect the level of tumor-derived extracellular vesicles using our method based on dual DNA tetrahedral nanostructures. The level of tumor-derived extracellular vesicles was significantly higher in newly diagnosed breast cancer patients than in nonneoplastic individuals at a cutoff value of 3.58 U/µL. For postoperative metastasis monitoring, the level of tumor-derived extracellular vesicles was significantly higher in breast cancer patients with metastasis than in those without metastasis at a cutoff value of 3.91 U/µL. Its efficacy of diagnosis and metastasis monitoring was superior to traditional tumor markers. Elevated level of tumor-derived extracellular vesicles served as a predictive biomarker for diagnosis and metastasis monitoring in breast cancer patients.

Roles of estrogen receptors during sexual reversal in Pelodiscus sinensis.

BACKGROUND: The Chinese soft-shelled turtle, Pelodiscus sinensis, exhibits distinct sexual dimorphism, with the males growing faster and larger than the females. During breeding, all-male offspring can be obtained using 17ß-estradiol (E2). However, the molecular mechanisms underlying E2-induced sexual reversal have not yet been elucidated. Previous studies have investigated the molecular sequence and expression characteristics of estrogen receptors (ERs). METHODS AND RESULTS: In this study, primary liver cells and embryos of P. sinensis were treated with ER agonists or inhibitors. Cell incubation experiments revealed that nuclear ERs (nERs) were the main pathway for the transmission of estrogen signals. Our results showed that ERα agonist (ERα-ag) upregulated the expression of Rspo1, whereas ERα inhibitor (ERα-Inh) downregulated its expression. The expression of Dmrt1 was enhanced after ERα-Inh + G-ag treatment, indicating that the regulation of male genes may not act through a single estrogen receptor, but a combination of ERs. In embryos, only the ERα-ag remarkably promoted the expression levels of Rspo1, Wnt4, and ß-catenin, whereas the ERα-Inh had a suppressive effect. Additionally, Dmrt1, Amh, and Sox9 expression levels were downregulated after ERß inhibitor (ERß-Inh) treatment. GPER agonist (G-ag) has a significant promotion effect on Rspo1, Wnt4, and ß-catenin, while the inhibitor G-Inh does not affect male-related genes. CONCLUSIONS: Overall, these results suggest that ERs play different roles during sexual reversal in P. sinensis and ERα may be the main carrier of estrogen-induced sexual reversal in P. sinensis. Further studies need to be performed to analyze the mechanism of ER action.

Hypoxia stimulates CTC-platelet cluster formation to promote breast cancer metastasis.

Circulating tumor cell clusters/micro-emboli (CTM) possess greater metastatic capacity and survival advantage compared to individual circulating tumor cell (CTC). However, the formation of CTM subtypes and their role in tumor metastasis remain unclear. In this study, we used a microfluidic Cluster-Chip with easy operation and high efficiency to isolate CTM from peripheral blood, which confirmed their correlation with clinicopathological features and identified the critical role of CTC-platelet clusters in breast cancer metastasis. The correlation between platelets and CTM function was further confirmed in a mouse model and RNA sequencing of CTM identified high-expressed genes related to hypoxia stimulation and platelet activation which possibly suggested the correlation of hypoxia and CTC-platelet cluster formation. In conclusion, we successfully developed the Cluster-Chip platform to realize the clinical capture of CTMs and analyze the biological properties of CTC-platelet clusters, which could benefit the design of potential treatment regimens to prevent CTM-mediated metastasis and tumor malignant progression.

Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy.

Glutathione peroxidase 4 (GPX4) emerges as a promising target for the treatment of therapy-resistant cancer through ferroptosis. Thus, there is a broad interest in the development of GPX4 inhibitors. However, a majority of reported GPX4 inhibitors utilize chloroacetamide as a reactive electrophilic warhead, and the selectivity and pharmacokinetic properties still need to be improved. Herein, we developed a compound library based on a novel electrophilic warhead, the sulfonyl ynamide, and executed phenotypic screening against pancreatic cancer cell lines. Notably, one compound A16 exhibiting potent cell toxicity was identified. Further chemical proteomics investigations have demonstrated that A16 specifically targets GPX4 under both in situ and in vivo conditions, inducing ferroptosis. Importantly, A16 exhibited superior selectivity and potency compared to reported GPX4 inhibitors, ML210 and ML162. This provides the structural diversity of tool probes for unraveling the fundamental biology of GPX4 and exploring the therapeutic potential of pancreatic cancer via ferroptosis induction.

Global Reactivity Profiling of the Catalytic Lysine in Human Kinome for Covalent Inhibitor Development.

Advances in targeted covalent inhibitors (TCIs) have been made by using lysine-reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell-active TCIs are however available. We report herein lysine-reactive activity-based probes (ABPs; 2-14) based on the chemistry of aryl fluorosulfates (ArOSO2 F) capable of global reactivity profiling of the catalytic lysine in human kinome from mammalian cells. We concurrently developed reversible covalent ABPs (15/16) by installing salicylaldehydes (SA) onto a promiscuous kinase-binding scaffold. The stability and amine reactivity of these probes exhibited a broad range of tunability. X-ray crystallography and mass spectrometry (MS) confirmed the successful covalent engagement between ArOSO2 F on 9 and the catalytic lysine of SRC kinase. Chemoproteomic studies enabled the profiling of >300 endogenous kinases, thus providing a global landscape of ligandable catalytic lysines of the kinome. By further introducing these aminophiles into VX-680 (a noncovalent inhibitor of AURKA kinase), we generated novel lysine-reactive TCIs that exhibited excellent in vitro potency and reasonable cellular activities with prolonged residence time. Our work serves as a general guide for the development of lysine-reactive ArOSO2 F-based TCIs.

Construction of a Low-Resistivity Carbon Layer To Improve Performance in Dimethyl Sulfoxide-Based Kesterite Solar Cells.

Morphology of the absorber plays a decisive role in photoelectric conversion efficiency (PCE) of kersterite solar cells. Cu2ZnSn(S,Se)4 (CZTSSe) grain prepared from dimethyl sulfoxide (DMSO)-based solution easily grows into large grains, which can lead to the formation of some holes at the back of the absorber. These holes cause the recombination of photocarriers and greatly weaken the performance of CZTSSe devices. Here, trace amounts of thioglycolic acid (TGA) are introduced to the DMSO-based solution, and a combination of TGA and metal is formed in the absorber, leading to the formation of fine grains in the CZTSSe absorber. Next, post-annealing (PA) in a N2 atmosphere is performed to promote Na diffusion, helping the transition from a fine-grain layer to a low-resistivity carbon layer at the interface between CZTSSe and Mo and avoiding the drawbacks of the DMSO-based system. Finally, the champion PCE of the CZTSSe device can be improved to 10.05% from 8.06%. The conclusions demonstrate that the construction of a carbon layer can boost the performance of CZTSSe devices.

Engineering the Tat-secretion pathway of Bacillus licheniformis for the secretion of cytoplasmic enzyme arginase.

The industrial bacterium Bacillus licheniformis has long been used as a microbial factory for the production of enzymes due to its ability to secrete copious amounts of native extracellular proteins and its generally regarded as safe (GRAS) status. However, most attempts to use B. licheniformis to produce heterologous and cytoplasmic enzymes primarily via the general secretory (Sec) pathway have had limited success. The twin-arginine transport (Tat) pathway offers a promising alternative for the extracellular export of Sec-incompatible proteins because it transports full, correctly folded proteins. However, compared to the Sec pathway, the yields of the Tat pathway have historically been too low for commercial use. To improve the export efficiency of the Tat pathway, we identified the optimal Tat-dependent signal peptides and increased the abundance of the Tat translocases, the signal peptidase (SPase), and the intracellular chaperones. These strategic modifications significantly improved the Tat-dependent secretion of the cytoplasmic enzyme arginase into the culture medium using B. licheniformis. The extracellular enzymatic activity of arginase showed a 5.2-fold increase after these modifications. Moreover, compared to the start strain B. licheniformis 0F3, the production of extracellular GFP was improved by 3.8 times using the strategic modified strain B. licheniformis 0F13, and the extracellular enzymatic activity of SOX had a 1.3-fold increase using the strain B. licheniformis 0F14. This Tat-based production chassis has the potential for enhanced production of Sec-incompatible enzymes, therefore expanding the capability of B. licheniformis as an efficient cellular factory for the production of high-value proteins. KEY POINTS: • Systematic genetic modification of Tat-pathway in B. licheniformis. • Significant enhancement of the secretion capacity of Tat pathway for delivery the cytoplasmic enzyme arginase. • A new platform for efficient extracellular production of Sec-incompatible enzymes.

Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism. METHODS: Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERß) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR. RESULTS: Based on the TNBC tissue array analysis, we revealed that ERß and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERß positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERß transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter -42 bp to -28 bp was an AR response element, and that ERß interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial-mesenchymal transition in tumor progression. CONCLUSIONS: This study suggests that ERß functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

Integrating High-Sensitivity Photodetector and High-Energy Aqueous Battery in All-in-One Triple-Twisted Fiber.

Fiber-shaped photodetectors (FPDs) have attracted special attention to wearable health monitoring due to their 3D absorption capabilities. However, the practical application of traditional FPDs is severely limited by the irreversible degradation of performance caused by vulnerable interface compatibility on complex deformation and a single function. Here, an integrated photoelectrochemical FPD/battery device (FPDB) is designed, consisting of a common electrode, photoanode, anode, and sol-gel electrolyte as an isolation layer, which not only effectively avoids the short circuit problem of FPD but also endows high-efficiency energy storage capacity. As expected, the resulting all-in-one triple-twisted fiber-shaped FPDB simultaneously achieves high responsiveness of 151.45 mA W-1 and excellent volume capacity of 18.75 mAh cm-3. Such a stable architectural design and multifunctional integration of functional fibers accelerate the development of next-generation wearable fabrics.

Multitarget inhibitors/probes that target LRRK2 and AURORA A kinases noncovalently and covalently.

Herein, we report a salicylaldehyde-based, reversible covalent inhibitor (A2) that possesses moderate cellular activity against AURKA with a prolonged residence time and shows significant non-covalent inhibition towards LRRK2. Our results indicated that this multitarget kinase inhibitor may be used as the starting point for future development of more potent, selective and dual-targeting covalent kinase inhibitors against AURKA and LRRK2 for mitophagy.

Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.